19-Hydroxy-19-methyl-inter-phenylene-PG1 compounds

ABSTRACT

The present invention provides novel 19-hydroxy-19-methyl-inter-phenylene-PG 1  compounds, methods for their preparation and pharmacological use for the induction of prostaglandin-like effect.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application is a division of Ser. No. 025,878, filed Apr. 2,1979, now U.S. Pat. No. 4,228,104.

BACKGROUND OF THE INVENTION

The present invention relates to novel prostaglandin analogs.Particularly, these compounds are analogs of the prostaglandins whereinthe C-19 position is substituted by hydroxy, i.e.,19-hydroxy-19-methyl-PG compounds. Most particularly, the presentinvention relates to novel 19-hydroxy-19-methyl-inter-phenylene-PG₁compounds, a disclosure of the preparation and use of which isincorporated here by reference from U.S. Pat. No. 4,228,104.

Prior Art

Prostaglandin analogs exhibiting hydroxylation in the 19-position areknown in the art. See, for example, U.S. Pat. No. 4,127,612, Sih, J. C.,Prostaglandins 13:831 (1977) and U.S. Pat Nos. 3,657,316, 3,878,046, and3,922,297. See also the additional references cited in U.S. Ser. No.025,878.

SUMMARY OF THE INVENTION

The present invention particularly provides:

a compound of the formula ##STR1## wherein D is (1) --(m--Ph)--(CH₂)₂--, or

(2) --(m--Ph)--O--CH₂ --,

wherein --(m--Ph)-- is inter-meta-phenylene, and

wherein Q is α-OH:β-R₅ or α-R₅ :β-OH, wherein R₅ is hydrogen or methyl;

wherein R₆ is

(a) hydrogen,

(b) alkyl of one to 12 carbon atoms, inclusive,

(c) cycloalkyl of 3 to 10 carbon atoms, inclusive,

(d) aralkyl of 7 to 12 carbon atoms, inclusive,

(e) phenyl,

(f) phenyl substituted with one, 2, or 3 chloro or alkyl groups of oneto 3 carbon atoms, inclusive,

(g) --(p--Ph)--CO--CH₃,

(h) --(p--Ph)--NH--CO--(p--Ph)--NH--CO--CH₃,

(i) --(p--Ph)--NH--CO--(p--Ph),

(j) --(p--Ph)--NH--CO--CH₃,

(k) --(p--Ph)--NH--CO--NH₂,

(l) --(p--Ph)--CH═N--NH--CO--NH₂,

(m) β-naphthyl,

(n) --CH₂ --CO--R₂₈,

wherein (p--Ph) is para-phenyl or inter-para-phenylene,

wherein R₂₈ is phenyl, p-bromophenyl, p-biphenylyl, p-nitrophenyl,p-benzamidophenyl, or 2-naphthyl, or

(o) a pharmacologically acceptable cation;

wherein R₂ is hydrogen, hydroxyl, or hydroxymethyl;

wherein R₃ and R₄ are hydrogen, methyl, or fluoro, being the same ordifferent, with the proviso that one of R₃ and R₄ is fluoro only whenthe other is hydrogen or fluoro;

wherein W is oxo, methylene, α-OH:β-H, or α-H:β-OH; and

wherein X is cis- or trans--CH═CH-- or --C.tbd.C--.

With regard to the divalent the substituents described above (e.g., Q)these divalent radicals are defined as α-R_(i) :β-R_(j), wherein R_(i)represents the substituent of the divalent moiety in the alphaconfiguration with respect to the ring and R_(j) represents thesubstituent of the divalent moiety in the beta configuration withrespect to the plane of the ring. Accordingly, when Q is defined asα-OH:β-R₅, the hydroxy of the Q moiety is in the alpha configuration,i.e., as in the natural prostaglandin, and the R₅ substituent is in thebeta configuration.

Specific embodiments of the present invention include:

19-hydroxy-19-methyl-3,7-inter-m-phenylene-PGF₁ α.

The compounds of the present invention are particularly useful forinducing prostaglandin-like biological effects, as is described in U.S.Ser. No. 025,878. Uses of compounds in accordance with the presentinvention include, therefore, anti-asthmatic indications.

I claim:
 1. A compound of the formula ##STR2## wherein D is (1)--(m--Ph)--(CH₂)₂ --, or(2) --(m--Ph)--O--CH₂ --,wherein --(m--Ph)-- isinter-meta-phenylene, and wherein Q is α-OH:β-R₅ or α-R₅ :β-OH, whereinR₅ is hydrogen or methyl; wherein R₆ is (a) hydrogen, (b) alkyl of oneto 12 carbon atoms, inclusive, (c) cycloalkyl of 3 to 10 carbon atoms,inclusive, (d) aralkyl of 7 to 12 carbon atoms, inclusive, (e) phenyl,(f) phenyl substituted with one, 2, or 3 chloro or alkyl groups of oneto 3 carbon atoms, inclusive, (g) --(p--Ph)--CO--CH₃, (h)--(p--Ph)--NH--CO--(p--Ph)--NH--CO--CH₃, (i) --(p--Ph)--NH--CO--(p--Ph),(j) --(p--Ph)--NH--CO--CH₃, (k) --(p--Ph)--NH--CO--NH₂, (l)--(p--Ph)--CH═N--NH--CO--NH₂, (m) β-naphthyl, (n) --CH₂--CO--R₂₈,wherein (p--Ph) is para-phenyl or inter-para-phenylene,wherein R₂₈ is phenyl, p-bromophenyl, p-biphenylyl, p-nitrophenyl,p-benzamidophenyl, or 2-naphthyl, or (o) a pharmacologically acceptablecation; wherein R₂ is hydrogen, hydroxyl, or hydroxymethyl; wherein R₃and R₄ are hydrogen, methyl, or fluoro, being the same or different,with the proviso that one of R₃ and R₄ is fluoro only when the other ishydrogen or fluoro; wherein W is oxo, methylene, α-OH:β-H, or α-H:β-OH;and wherein X is cis- or trans--CH═CH-- or --C.tbd.C--. 2.19(R)-19-hydroxy-19-methyl-3,7-inter-m-phenylene-PGF₁ α, a compoundaccording to claim 1.